This article addresses the spectrum of atypia and dysplasia within the bladder epithelium and the diagnostic categories developed to further classify challenging lesions. In addition, the effects of inflammation, specific therapies, and instrumentation on the bladder mucosa as well as the associated difficulty in achieving the appropriate diagnosis are also discussed.
Key points
- •
Atypia and dysplasia are terms used to describe cellular abnormalities in the spectrum of reactive changes to neoplasia.
- •
Acute and chronic inflammation secondary to infectious, mechanical, or idiopathic causes can induce cytologic and architectural changes that can be interpreted by pathologists within the spectrum of atypia.
- •
Treatments, including systemic chemotherapy, intravesicular therapy, and radiotherapy, incite specific, often common, cellular changes that can microscopically be concerning for a neoplastic process.
- •
Despite improved investigation, the utility of immunohistochemistry as an ancillary tool in distinguishing benign processes from urothelial neoplasia remains unclear.
Introduction
The urothelial lining of the bladder presents diagnostic challenges, even under normal circumstances. A multitude of confounding factors, such as inflammation, reparative changes, distension state, and treatment effects, can hinder a diagnosis of early neoplasia. Thus, evaluation of biopsy and/or transurethral resection specimens requires pathologists to command a detailed understanding of the spectrum of histologic changes that can arise in the urinary bladder. Adding to the diagnostic challenge is that available ancillary studies, such as immunohistochemical (IHC) stains, are suboptimal in the diagnosis of bladder neoplasia. In light of these difficulties, pathologists have developed several diagnostic categories to address the histologic gray zones in bladder pathology. Despite what progress has been made, these categories are subjective and often do not correlate with outcomes.
Introduction
The urothelial lining of the bladder presents diagnostic challenges, even under normal circumstances. A multitude of confounding factors, such as inflammation, reparative changes, distension state, and treatment effects, can hinder a diagnosis of early neoplasia. Thus, evaluation of biopsy and/or transurethral resection specimens requires pathologists to command a detailed understanding of the spectrum of histologic changes that can arise in the urinary bladder. Adding to the diagnostic challenge is that available ancillary studies, such as immunohistochemical (IHC) stains, are suboptimal in the diagnosis of bladder neoplasia. In light of these difficulties, pathologists have developed several diagnostic categories to address the histologic gray zones in bladder pathology. Despite what progress has been made, these categories are subjective and often do not correlate with outcomes.
What are atypia and dysplasia?
The definition of atypia has been a contentious topic within the field of pathology, not restricted to the genitourinary subspecialty. The lack of consensus on one of the most commonly used terms in pathology can be attributed to a variety of causes, such as the subjective nature of histologic evaluation, institutional bias, prior diagnosis, and preference of the evaluating pathologist. Furthermore, some pathologists have used the terms, atypia and dysplasia , interchangeably, which can introduce problems in clinical management. It is implied that atypia represents a benign process in many instances whereas dysplasia describes a preneoplastic/neoplastic process, although variation in defining these categories at the microscopic level often leads to confusion.
From a histologic perspective, atypia refers to a presence of 1 or more cellular or architectural features that deviate from that of an otherwise normal-appearing cell or group of cells. Under normal conditions, urothelial cells contain oval nuclei, finely stippled chromatin, and minute to absent nucleoli as well as ample cytoplasm and distinct cell membranes ( Fig. 1 ). Even within the spectrum of normal, urothelial cells are permitted to have certain variations in cell size and cytoplasm, particularly in the most superficial layer of the urothelium (umbrella cell layer), which is in constant contact with the contents of the urinary space. These umbrella cells tend to be larger than cells in the intermediate and basal layers, with occasional binucleation and abundant eosinophilic cytoplasm. To further complicate matters for pathologists, bladder distension can lead to flattening of superficial (or umbrella) cells to a point where the layer can be difficult to identify microscopically.
Despite the variety of appearances of normal urothelial cells, certain specific cellular features are evaluated when determining the presence of atypia. Abnormal nuclear features, including increased size (nucleomegaly), deviation from typical ovoid shape, coarse chromatin, and irregular nuclear membrane contour, are all contributory factors in classifying cells as atypical ( Fig. 2 ). In addition, the identification of an enlarged, prominent nucleolus or multiple nucleoli should raise concern. Although eosinophilic (pink-appearing) cytoplasmic features are acceptable in the superficial urothelium, these cytoplasmic changes in other layers, as well as loss of cytoplasmic clearing, are also considered atypical features.
Although atypia often refers specifically to cytologic (cellular) abnormalities, architectural changes can also guide pathologists to the appropriate diagnosis. Denudation of the urothelium can be associated with previous instrumentation, inflammation, or a neoplastic process ( Fig. 3 ). Conversely, thickening (hyperplasia) of the epithelium can result from a variety of causes, ranging from a benign proliferation to a reactive process secondary to inflammation, as well as being simply an artifact of tangential sectioning. The presence of atypical cells in the background of varied epithelial thickness can pose a difficult diagnostic challenge. Assessment of histologic changes throughout the entire specimen, detailed clinical history, and cystoscopic findings are all necessary to ensure that correct diagnosis is made. As such, close communication with the treating urologist is critical for the appropriate diagnosis and management of a patient.
Diagnostic categories of flat urothelial lesions
Reactive Urothelial Atypia
Reactive urothelial atypia remains one of the broadest categories used to describe abnormal-appearing urothelium but is generally considered at diagnosis to represent a benign process. Reactive atypia is most often diagnosed in the setting of an acute and/or chronic inflammatory process that may arise in the setting of past instrumentation, infection, prior treatment, and other clinical scenarios that incite inflammation. The cytologic and architectural abnormalities that arise in these contexts are generally mild and uniform. Increased nuclear size, vesicular-appearing chromatin, and pinpoint nucleoli are the most common features identified microscopically with reactive changes, which often occur in the presence of an inflammatory infiltrate within the urothelium ( Fig. 4 ). A key distinction for reactive atypia is uniformity of findings throughout the specimen. Pleomorphism (variation in nuclear size), hyperchromasia, and nuclear crowding are features that should raise concern for a probable preneoplastic or overt neoplastic process.
Atypia of Unknown Significance
Atypia of unknown significance is a term introduced by an International Society of Urological Pathology consensus group in 1998 to classify histologic findings that meet various criteria for both reactive changes and dysplasia. Typically, this diagnosis is used in the setting of reactive nuclear and cytoplasmic changes with mild degrees of pleomorphism and/or hyperchromasia that are concerning for dysplasia. Additionally, this term has been used to describe histologic findings where the level of atypia is disproportionally greater than expected for the amount of inflammation. There is ongoing debate on whether this term is even an appropriate diagnosis. The classification of histologic findings as atypia of unknown significance warrants clinical follow-up, ideally in the setting of resolved inflammation. Despite the inclination to monitor these patients prospectively, there is no evidence in the literature that has shown that this category of patients is predisposed to neoplastic progression, although further studies are needed to better clarify this entity.
Urothelial Dysplasia
Urothelial dysplasia is considered to represent early preneoplastic/neoplastic change, with histologic features beyond those considered in the spectrum of benign or reactive urothelium. In dysplasia, the thickness of the urothelium can be variable, but umbrella cells are usually present. Features of cellular crowding, multiple nucleoli, and mild hyperchromasia are common in this diagnostic category ( Fig. 5 ). The diagnosis of dysplasia is used when some, but not all, of the criteria necessary for urothelial carcinoma in situ (CIS) are met. Currently, further subclassification of dysplasia as mild grade or moderate grade is no longer commonplace, whereas severe dysplasia is generally considered CIS.
Urothelial dysplasia can be further categorized into primary (de novo) and secondary dysplasia. Primary dysplasia is defined as dysplasia occurring in the absence of other histologic features of CIS and with no precedent history of urothelial neoplasia. Because patients are usually asymptomatic and/or no gross lesion is visible on cystoscopy, true primary dysplasia is rarely seen by pathologists. Secondary dysplasia is classified as dysplasia identified in the setting of known neoplasia of the bladder, either current or prior. In either presentation, patients are currently undergoing screening to assess current symptoms or monitoring of a precedent high-grade lesion. Although both primary and secondary dysplasia are classified as true premalignant lesions, secondary dysplasia is more likely to progress to carcinoma.
Carcinoma in Situ
Urothelial CIS is a neoplastic diagnosis, with malignant cells restricted within the urothelial lining of the bladder (noninvasive disease). In addition to the features of dysplasia, these cells demonstrate marked nuclear and cellular pleomorphism and hyperchromasia ( Fig. 6 ). CIS is commonly underdiagnosed when full-thickness cytologic atypia is absent or when umbrella cells are identified. Underdiagnosis of CIS may also occur in the setting of clinging CIS (single carcinoma cells are present in a background of otherwise denuded urothelium) and subtle involvement of von Brunn nests by CIS cells.
Inflammation as a contributor to a diagnosis of atypia/dysplasia
There are many inflammatory and infectious processes that incite reactive changes within the urinary bladder. Specifically, acute and chronic inflammation secondary to infectious, mechanical, or idiopathic causes can induce cytologic and architectural changes that can be interpreted by pathologists within the spectrum of atypia. The following categories represent a sampling of some of the common inflammatory processes that often lead to a diagnosis of atypia and/or dysplasia on bladder biopsy.
Acute and Chronic Cystitis
The most common cause of acute cystitis is infection, primarily, but not restricted to, gram-negative bacteria. Additional causes of acute cystitis include prior instrumentation, trauma, and catheterization. In the acute setting, inflammatory-mediated cell responses lead to an influx of neutrophils, lymphocytes, and macrophages within the urothelium and lamina propria of the bladder. Edema and vascular congestion are also common. Although reactive changes of the urothelium may not occur until the subacute or chronic inflammatory phase, pronounced inflammation can obscure underlying pathologic processes and make assessment difficult for pathologists, thus leading to a diagnosis of atypia. In the setting of chronic cystitis, a variety of changes can occur in the urothelium, including denudation, ulceration, or hyperplasia. In addition to difficulties in adequately visualizing the specimen microscopically secondary to copious amounts of granulation tissue and/or fibrosis, reactive atypia due to a persistent inflammatory process can raise suspicion for dysplasia in the bladder.
Polypoid Cystitis
Polypoid cystitis, a common variant of cystitis in the bladder, remains a challenging inflammatory lesion for pathologists and urologists alike ( Fig. 7 ). On cystoscopy, the often exophytic growth pattern of polypoid cystitis may clinically resemble a papillary neoplasm. These lesions tend to appear in patients with a history of indwelling catheters, fistulas, chronic obstruction, or calculi. Microscopically, the lesion consists of large, bulbous outpouchings of the urothelial lining, with the lamina propria often edematous ( Fig. 8 ). Over time, ongoing inflammation may produce scarring of the lamina propria, leading to a more papillary-like appearance as well as inducing squamous metaplasia and reactive atypia. In a 2008 study, 41 cases of polypoid cystitis previously misdiagnosed as papillary urothelial neoplasia were rereviewed. Despite some mild atypia and mitotic figures in many of the cases, the cytologic features included uniform cell enlargement, similar vesicular chromatin patterns, and a single prominent nucleolus. Each of the 41 cases lacked definitive hyperchromasia and nuclear pleomorphism, which are key criteria in differentiating benign, reactive lesions from neoplasia.
Related posts:
Perioperative Chemotherapy
Office-based Bladder Tumor Fulguration and Surveillance
New Agents for Bacillus Calmette-Guérin–Refractory Bladder Cancer
The Conundrum of Prostatic Urethral Involvement
The Costs of Non-Muscle Invasive Bladder Cancer
New Imaging Techniques for Non-Muscle Invasive Bladder Cancer
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
